The olfactory system is critical for survival, and in humans, diminished sensory capacity seen with aging, injury, or degenerative diseases compromises health and the quality of life. Olfactory sensory neurons (OSNs) are the initial site of odorant detection, and thus their survival is critical for olfactory function. While progress has been made regarding the mechanisms that mediate odorant detection in OSNs, less is known about the factors that are critical for OSN survival. Our studies demonstrate that, in addition to the rapid signaling for odor detection, sensory stimulation induces long-term responses that may support neuronal survival. Our recent data suggest that odorant detection and sensory stimulation-driven survival proceed by parallel pathways. Furthermore, we found that sensory stimulation evokes cellular stress, which is exacerbated when sensory stimulation-activated pathways are inhibited. Our overall hypothesis is that sensory stimulation activates multiple signal transduction cascades in parallel to those that serve stimulus detection to promote neuronal survival and to respond to activity-induced cellular stress. Loss of these responses to sensory stimulation exacerbates activity- related stress, leading to progressive cell damage and ultimately neuronal death. The overall goal of this proposal is to delineate the signal transduction pathways that mediate sensory stimulation driven survival and stress responses. We employ molecular and cell biological approaches using in vitro and in vivo models to investigate testable hypotheses. Aim 1 will utilize in vitro cultures, in vivo sensory stimulation and deprivation models, and biochemical and genetic approaches to delineate the mechanisms of the MEK/Erk and PI3K/Akt signaling pathways that contribute to sensory stimulus-dependent OSN survival. Aim 2 will use these models to study the divergence of odorant detection pathways and activity-dependent OSN survival. Aim 3 will utilize in vitro and in vivo models of sensory stimulation and deprivation, and biochemical and genetic approaches to study the effects of sensory-induced stress on OSN survival and the pathways that are involved. The rationale for these studies is that understanding the factors that regulate the survival of OSNs is essential for strategies aimed at preserving olfactory function. These findings have the potential to provide a basis for the development of therapeutic strategies to rescue neurons from death in response to injury and thus preserve olfactory function.